Hepcidin, a peptide hormone produced by the liver, is a regulator of iron metabolism and controls the transfer of iron from iron stores or the diet to red blood cells for incorporation into hemoglobin in humans and other mammals. Hepcidin acts by binding to the iron export channel ferroportin, and causing its internalization and degradation. When hepcidin removes ferroportin from the cell surface, the transfer or iron from either cellular stores within the body or dietary content in the intestine is prevented. Human hepcidin is a 25-amino acid peptide (Hep25). See Krause et al. (2000) FEBS Lett 480: 147-150, and Park et al. (2001) J Biol Chem 276:7806-7810, which is hereby incorporated by reference in its entirety and, for example, for the sequence of Hep25. The structure of the bioactive 25-amino acid form of hepcidin is a hairpin with 8 cysteines that form 4 disulfide bonds as described by Jordan et al. (2009) J Biol Chem 284:24155-67, which is hereby incorporated by reference in its entirety and, for example, for the structure and other information about the sequence. The N-terminal region has been shown to be required for iron-regulatory function, and deletion of 5 N-terminal amino acid residues results in a loss of iron-regulatory function (Nemeth et al. (2006) Blood 107:328-33). This finding has resulted in the design of drug-like hepcidin mimetic peptides (Preza et al., Clin Invest. 2011; 121(12):4880-4888).
Since either deficiency or excess of iron results in disease, hepcidin levels vary in order to maintain iron stores within a physiologically acceptable range. When hepcidin levels are abnormally low, iron transfer through ferroportin is correspondingly high. Consequently iron absorption from the diet is unrestricted and severe iron overload may develop that causes cell damage and organ failure. Conversely, when hepcidin levels are abnormally high, restriction in iron transfer to the developing red cell can cause reduction in erythropoiesis and eventually result in anemia.
Hepcidin mimetic peptides have potential use in a number of different hematological and metabolic diseases in which hepcidin levels are abnormally low including iron loading anemias and hereditary hemochromatosis. Iron-loading anemias such as beta thalassemia and myelodysplastic syndrome are characterized by the presence of ineffective erythropoiesis which contributes to severe anemia and also causes a reduction in hepcidin production, leading to severe iron overload. Complications from iron overload are a major cause of morbidity and mortality for these patients. Hepcidin deficiency is the main cause of iron overload in untransfused patients, and contributes to iron overload in transfused patients. The current treatment for iron overload in these patients is iron chelation which is very burdensome, sometimes ineffective and accompanied by frequent side effects.
Additionally, abnormally low hepcidin levels are associated with other iron overload diseases such as hereditary hemochromatosis or chronic liver disease. Hereditary hemochromatosis (HH) is a genetic iron overload disease that is mainly caused by hepcidin deficiency, or very rarely by hepcidin resistance. This allows excessive absorption of iron from the diet and development of iron overload. Clinical manifestations of HH may include liver disease (hepatic cirrhosis, hepatocellular carcinoma), diabetes, and heart failure. Currently, the only treatment for HH is regular phlebotomy, which is effective but very burdensome for the patients.
Hepcidin mimetic peptides may also be used to regulate the rate of erythropoiesis in diseases where abnormally accelerated erythropoiesis is present, such as polycythemia vera.
The use of hepcidin mimetic peptides for the treatment of such diseases requires compounds that are highly active in producing hepcidin activity following administration but which are sufficiently stable and soluble to be appropriately formulated for administration. There is still a need for compounds to treat such conditions. The embodiments disclosed herein satisfy these needs and others.